Certain aza-bicyclo-benzamide derivatives and pharmaceutical compositions containing same

ABSTRACT

Substituted benzamides having useful pharmacological properties, pharmaceutical compositions containing the same, pharmaceutically acceptable salts thereof, and procedure for administering said compositions. The active compounds have dopamine antagonist activity which is an effective amount of a compound of formula (I) and the compositions are particularly useful for the treatment of humans suffering from emesis impaired gastro-intestinal motility and disorders of the central nervous system. The administration of the compositions overcomes these disorders of the central nervous system and ordinary additions. The active compounds are characterized by having the formula (I), wherein R 2  and/or R 3  are sulphone groups, preferably either R 2  or R 3  being an aminosulphone or alkylsulphone group, which groups may optionally be substituted by 1 or 2 C 1-6  alkyl groups.

CROSS-REFERENCE

This is a division of Ser. No. 107,413, filed Dec. 26, 1979, now U.S.Pat. No. 4,273,778.

This invention relates to novel substituted benzamides having usefulpharmacological properties, to pharmaceutical compositions containingthem, and to a process for their preparation.

N-(2-Diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide,1-ethyl-2(2-methoxy-5-sulphamoylbenzamidomethyl)pyrrolidine andN-[4'-(1"-benzyl)-piperidyl]-2-methoxy-4-amino-5-chlorobenzamide arewell known compounds having useful pharmacological activity such as theability to regulate the gastro-intestinal function anti-emetic activityand CNS activity.

It has now been found that a certain structurally distinct class ofsubstituted benzamides also has useful pharmacological activity, inparticular dopamine antagonist activity.

Accordingly, the present invention provides a compound of the formula(I), and pharmaceutically acceptable salts thereof: ##STR1## wherein: R₁is a C₁₋₆ alkoxy group;

R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇acyl, C₂₋₇ acylamino, or amino, aminocarbonyl or aminosulphoneoptionally substituted by one or two C₁₋₆ alkyl groups, C₁₋₆alkylsulphone or nitro;

R₅ is hydrogen or C₁₋₆ alkyl;

R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 0 to 2 and R₇ is aC₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₈ where t is 1 or 2 andR₈ is C₂₋₅ alkenyl or a phenyl group optionally substituted by one ortwo substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyland halogen; and

n, p and q are independently 0 to 2.

Suitable examples of the group R₁ include methoxy, ethoxy and n- andiso-propoxy. Preferably R₁ is a methoxy group.

Suitable examples of the groups R₂ and R₃ include the following groups:hydrogen, chlorine, bromine, CF₃, acetyl, propionyl, n- and iso-butyryl,acetylamino, propionylamino, n- and iso-butyrylamino, amino,aminocarbonyl, aminosulphone, amino, aminocarbonyl and aminosulphonesubstituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec- ortert-butyl groups; and methyl, ethyl or n- and iso-propylsulphones, andnitro.

Particularly suitable R₂ and R₃ groups include hydrogen, halogen, acyl,amino, and acylated amino as defined.

It is generally preferred that R₂ is in the 4-position relative to thecarbonyl side chain for greater activity in the resultant compound ofthe formula (I). For the same reason it is generally preferred that R₃is in the 5-position relative to the carbonyl side chain.

Particularly preferred R₂ groups include 4-amino and 4-(acylated amino)as defined. Preferably R₂ is 4-amino. Particularly preferred R₃ groupsinclude 5-halo, such as 5-chloro.

Often the amide and side chain nitrogen atoms are separated by a minimumof 2 or 3 carbon atoms, preferably 3.

Suitable examples of R₅ include hydrogen, methyl, ethyl, n- andiso-propyl, n-, sec- and tert-butyl, preferably hydrogen or methyl, inparticular hydrogen.

Suitable examples of R₆ when C₁₋₇ alkyl include methyl, ethyl, n- andiso-propyl and n-, sec-, iso- and tert-butyl, n-pentyl, n-hexyl andn-heptyl.

Within C₁₋₇ radicals, C₁₋₄ alkyl are particularly useful (as hereinafterdescribed).

Suitable examples of R₆ when C₁₋₄ alkyl include methyl, ethyl, n- andiso-propyl and n-, sec-, iso- and tert-butyl, particularly methyl,n-propyl and iso-butyl.

Similarly, within C₁₋₇ radicals, C₅₋₇ alkyl are also of interest (ashereinafter described).

Suitable examples of R₆ when C₅₋₇ alkyl include n-pentyl, n-hexyl andn-heptyl.

When R₆ is a group --(CH₂)_(s) R₇ as defined, suitable examples of R₇include C₅₋₈ cycloalkyl, preferably cyclohexyl. s is preferably 1.

When R₆ is a group --(CH₂)_(t) R₈ as defined, t is preferably 1.

In such a group R₆, when R₈ is C₂₋₅ alkenyl, suitable examples thereofinclude vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl,but-2-enyl, but-3-enyl, 1-methylenepropyl, 1-methylprop-1-enyl and1-methylprop-2-enyl, in their E and Z forms where stereoisomerismexists.

A preferred C₁₋₅ alkenyl R₈ radical is vinyl, so that R₆ is preferablyallyl.

When R₈ is optionally substituted phenyl as defined above, suitableexamples of such optional phenyl substituents include methyl, ethyl, n-and iso-propyl, n, sec- and tert-butyl; methoxy, ethoxy, n- andiso-propoxy; CF₃, fluoro, chloro or bromo. Preferably R₈ when optionallysubstituted phenyl is unsubstituted.

Compounds of the formula (I) wherein R₆ is --(CH₂)_(s) R₇ and--(CH₂)_(t) R₈ as defined, and wherein R₆ contains at least 5 carbonatoms, are of particular interest because of their beneficialpharmacological activity (as hereinafter discussed). In such compoundsR₆ is preferably benzyl.

n is preferably 0. q is suitably 0 to 1, preferably 1. p is suitably 0to 1, preferably 0.

It is greatly preferred for higher activity that the bond between thebenzamide moiety and the cyclic side chain (ie between the R₅substituted nitrogen atom and the (CH₂)_(n) moiety) in the compounds offormula (I) is equatorial.

The pharmaceutically acceptable salts of the compounds of the formula(I) include acid addition salts with conventional acids such ashydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric,lactic and acetic acid and the like.

The pharmaceutically acceptable salts of the compounds of the formula(I) also include quaternary ammonium salts. Examples of such saltsinclude such compounds quaternised by compounds such as R₉ -Y wherein R₉is C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and Y is an anionof an acid. Suitable examples of R₉ include methyl, ethyl and n- andiso-propyl; and benzyl and phenylethyl. Suitable examples of Y includethe halides such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internalsalts such a N-oxides.

The compounds of the formula (I) can also form hydrates.

A group of compounds within those of the formula (I) consists of thosewherein:

R₁ is a C₁₋₆ alkoxy group;

R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇acyl, amino, C₂₋₇ acyl amino, aminocarbonyl or aminosulphone optionallysubstituted by one or two C₁₋₆ alkyl groups; C₁₋₆ alkylsulphone or nitrogroups;

R₅ is hydrogen or C₁₋₆ alkyl;

R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 1 or 2 and R₇ is aC₃₋₈ cycloalkyl group, or a phenyl group optionally substituted by oneor two substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy,trifluoromethyl and halogen; and

n, p and q are independently 0 to 2.

From the aforesaid it will be seen that in a preferred aspect the moietyof formula (II): ##STR2## in a compound of the formula (I) will have thestructure (III): ##STR3## In a preferred group of compounds within thoseof formula (I) and pharmaceutically acceptable salts thereof, the moietyof formula (II) will be of the formula (III), and the moiety of formula(IV): ##STR4## will have the formula (V): ##STR5## wherein the variablesare as defined in formula (I), so that these preferred compounds of theformula (I) are of the formula (VI): ##STR6## wherein the variables areas defined in formula (I).

More suitably p is 0 or 1, it is believed preferably 0. Preferably q is1 and the moiety of formula (III) is then attached at a position para tothe N-atom.

Suitable and preferred examples of R₆ in formula (VI) include thoselisted under formula (I) for R₆. Particularly preferred examples of R₆include C₁₋₇ alkyl and cyclohexylmethyl. Particularly preferred examplesof R₆ also include benzyl optionally substituted in the phenyl ring asdefined under formula (I). Unsubstituted benzyl is especially preferred.

A particularly preferred sub-group of compounds within those of formula(VI) are those of the formula (VII): ##STR7## wherein R₆ ¹ is C₁₋₄alkyl.

Suitable examples of R₆ ¹ are as so described for R₆ C₁₋₄ alkyl underformula (I).

It is preferred that the moiety of the formula (III) is in theβ-orientation to the nortropane ring.

Another particularly preferred sub-group of compounds within those offormula (VI) are those of the formula (VIII): ##STR8## wherein R₆ ² isC₅₋₇ alkyl; a group --(CH₂)_(t) R₈ ¹ wherein t is 1 or 2 and R₈ ¹ isoptionally substituted phenyl as defined in formula (I); orcyclohexylmethyl.

Suitable and preferred R₆ ² are as so described for the corresponding R₆groups under formula (I).

R₆ ² benzyl is especially preferred.

It is preferred that the moiety of the formula (III) is in theβ-orientation to the nortropane ring.

A sub-group of compounds within those of the formula (VI) of interestare those of the formula (IX): ##STR9## wherein R₆ ¹ is as defined informula (VII).

Suitable examples of R₆ ¹ are as so described under formula (VII).

Another sub-group of compounds within those of the formula (VI) ofinterest are those of the formula (X): ##STR10## wherein R₆ ¹ is asdefined in formula (VIII).

Suitable and preferred examples of R₆ ² are as so described underformula (VIII).

In a second group of compounds of interest the moiety of formula (II)will have the structure (III) as hereinbefore depicted and defined, butthe moiety of formula (IV) will have the structure (XI): ##STR11##wherein n' is 1 or 2 and the remaining variables are as defined informula (I).

More suitably p and q independently are 0 or 1; preferably p is 0 and qis 1.

Suitable and preferred examples of R₆ include those listed hereinbeforefor R₆. Particularly preferred examples of R₆ include benzyl optionallysubstituted in the phenyl ring as defined under formula (I).Unsubstituted benzyl is especially preferred.

Particularly suitable examples of the compounds of the present inventioninclude those specifically prepared in the Examples which form a latersection in this specification. These are:

4-acetamido-5-chloro-2-methoxy-N-(3α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1.]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-methyl-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-methyl-(3'-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

5-sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzylmethobromide

4-amino-5-chloro-2-methoxy-N-(3α'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3β'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-methylbenzyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-methoxybenzyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-ethoxybenzyl[-8'-azabicyclo-[3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-chlorobenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[3",4"-dichlorobenzyl]-8'-azabicyclo-(3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-methyl-8'-azabicyclo[3.2.1]-octyl])-benzamide

4-acetamido-5-chloro-2-methoxy-N-(3'α-[8'methyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[9'-methyl-9'-azabicyclo[3.3.1]nonyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[9'-methyl-9'-azabicyclo[3.3.1]-nonyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-ethyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-iso-propyl-8'-azabicyclo[3.2.1-octyl])benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-secbutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-isobutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexylmethyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl]benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-allyl-8-azabicyclo[3.2.1]octyl])benzamide,

5-chloro-2-methoxy-4-methylamino-N-(3β-[8'-benzyl-8-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-methyl-"-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(+)-α-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(-)-α-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(+)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide,and

4-amino-5-chloro-2-methoxy-N-(4'-(-)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide

It will of course be realised that the compounds of the formula (I) havechiral or prochiral centres, and thus are capable of existing in anumber of stereoisomeric forms. The invention extends to each of thesestereoisomeric forms, and to mixtures thereof (including racemates). Thedifferent stereoisomeric forms may be separated one from the other bythe usual methods, or any given isomer may be obtained by stereospecificor asymmetric synthesis.

The invention also provides a process for the preparation of a compoundof the formula (I), which process comprises reacting an acid of theformula (XII): ##STR12## or a reactive derivative thereof, with acompound of formula (XIII): ##STR13## wherein R₁₀ is hydrogen or R₆ asdefined in formula (I), the remaining variable groups being as definedin formula (I); and thereafter if desired or necessary converting agroup R₂ or R₃ in the thus formed compound to another group R₂ or R₃respectively; converting R₁₀ when hydrogen to R₆ ; and optionallyforming a pharmaceutically acceptable salt of the resultant compound ofthe formula (I).

`Reactive derivative` when used herein means a derivative of thecompound (XII) which can be reacted with the compound (XIII) to form anamido linkage between the acid group of the compound (XII) and the aminogroup of the compound of the formula (XIII).

Often this reactive derivative will be the acid halide, such as the acidchloride, of the acid (XII). In such cases, the reaction will normallybe carried out in an inert solvent, preferably in the presence of anacid acceptor. The inert solvent can be any solvent inert to bothreactants, such as benzene, toluene, diethyl ether or the like. The acidacceptor is suitably an organic base such as a tertiary amine e.g.triethylamine, trimethylamine, pyridine or picoline, or an inorganicacid acceptor, such as calcium carbonate, sodium carbonate, potassiumcarbonate or the like. It should also be noted that it is possible touse certain acid acceptors as the inert solvent, for example organicbases.

Another useful reactive derivative of the acid (XII) that may be used isan ester, such as a methyl, ethyl, propyl or butyl ester, in which casethe reaction is normally carried out by heating the reactants togetherin an inert solvent such as ethylene glycol.

The reaction may also be carried out by forming an anhydride of the acid(XII) in the usual manner, and reacting that with the compound (XIII);normally a conventional mixed anhydride will be used; or by reacting theacid (XII) and the compound (XIII) in the presence of a dehydratingcatalyst such as a carbodiimide, for example dicyclohexylcarbodiimide.

The intermediates of the formulae (XII) and (XIII) are either knowncompounds or can be prepared by analogous processes to known compounds.

It will be realised that in the compound of the formula (I) the--CO--NR₅ --(CH₂)_(n) -- linkage may have an α or β orientation withrespect to the ring of the bicyclic moiety to which it is attached. Amixture of α and β isomers of the compound of the formula (I) may besynthesised nonstereospecifically and the desired isomer separatedconventionally therefrom, e.g. by chromatography; or alternatively the αor β isomer may if desired be synthesised from the corresponding α or βform of the compound of the formula (XIII).

Synthesis from the corresponding α or β isomer of the compound of theformula (XIII) is in general preferred.

The α or β form of the compound of the formula (XIII) may if desired beprepared by known stereospecific processes, such as those leading to theα or β isomers of the compound of the formula (XIII) depicted in theScheme and described in Descriptions 3C, 4A and 4C and Descriptions 2and 3A and B respectively.

The precursor of the compound of the formula (XIII) may bestereospecifically synthesised, such as the azide (D3) of Description 2,and then converted to the corresponding desired isomer of the compoundof the formula (XIII) under nonstereospecific conditions with retentionof configuration. Alternatively, the precursor may itself have noasymmetiric centre at the relevant position, such as the oximes andimines of Descriptions 3 and 4, but be converted under stereospecificconditions to the desired isomer of the compound of the formula (XIII).

Alternatively, a mixture of the α and β isomers of the compound of theformula (XIII) may be synthesised nonstereospecifically and the desiredisomer separated conventionally therefrom e.g. by chromatography.However, in this case it is generally more convenient to react themixture to give a mixture of α and β isomers of the compound of theformula (I) and to separate these if desired as hereinbefore described.

The following Scheme 1 illustrates stereospecific and non-stereospecificsynthetic routes to intermediates of the formula (XIII) wherein n is 0.##STR14## The following Scheme 2 illustrates preparative routes tointermediates of the formula (XIII) wherein n is 1 or 2. ##STR15##

The acid addition salts of compounds of the formula (I) may be preparedin entirely conventional manner by reacting a compound of the formula(I) in base form with the chosen acid.

The quaternary ammonium salts of the compounds of the formula (I) may beprepared in conventional manner for such salts, such as by reaction ofthe chosen compound of the formula (I) with a compound R₉ Y as defined.This reaction is suitably carried out in an appropriate solvent such asacetone, methanol, ethanol, dimethylformamide and the like, at ambientor raised temperature and pressure.

The nitrogen atom of the moiety of formula (IV) may also form an N-oxideto give an intermal N-oxide salt of the compound of the formula (I). TheN-oxides may be prepared in conventional manner such as by reaction ofthe chosen compound of the formula (I) with an organic per-acid, such asm-chloroperbenzoic acid. This reaction is suitably carried out atbelow-ambient temperature in an organic solvent, preferably achlorinated hydrocarbon solvent.

The interconversion of suitable groups R₂ and R₃ after formation of acompound of the formula (I) or corresponding intermediate therefor maybe carried out by conventional methods. By way of example nitro groupsmay be reduced to amino groups in the normal manner, and acylaminogroups may be converted to amino groups also by conventional methods.Also a compound of the formula (I) wherein R₂ or R₃ is halogen can beprepared by a conventional halogenation of the corresponding compound ofthe formula (I) wherein the said R₂ or R₃ is hydrogen. Accordingly itwill be realised that compounds of the formula (I) containing an R₂ orR₃ group which is convertible to another R₂ or R₃ group are usefulintermediates, and as such form an important aspect of the invention.

Conversion of R₁₀ when hydrogen to a group R₆ as hereinbefore definedmay be carried out conventionally, for example by reacting the productof the reaction of the compounds of the formulae (XII) and (XIII) with acompound QR₆ wherein R₆ is as defined in formula (I) and Q is a group oratom readily displaced by a nucleophile.

Suitable values for Q include Cl, Br, I, OSO₂ CH₃ or OSO₂ C₆ H₄ pCH₃.

Favoured values for Q include Cl, Br and I.

Particularly suitably the compound QR₄ is a benzyl halide such as benzylbromide or benzyl chloride.

The reaction may be carried out under conventional alkylation conditionsfor example in an inert solvent such as dimethylformamide in thepresence of an acid acceptor such as potassium carbonate. Generally thereaction is carried out at a non-extreme temperature such as at ambientor at a slightly elevated temperature.

It will be appreciated that, when R₂ or R₃ are converted to other R₂ orR₃ and R₅ being hydrogen is converted to R₄, then these conversions maytake place in any desired or necessary order.

As hereinbefore stated, the compounds of the formula (I) are dopamineantagonists.

Depending on their balance between peripheral and central action, thecompounds of the formula (I) may be used in the treatment of disordersrelated to impaired gastro-intestinal motility, such as retarded gastricemptying, dyspepsia, flatulence, oesophagal reflux, peptic ulcer andemesis, and/or in the treatment of disorders of the central nervoussystem, such as psychosis.

All the compounds of the formula (I) may be used in the treatment ofemesis.

Examples of compounds of the formula (I) which are of particularinterest for their motility enhancing activity are those wherein R₆contains 1 to 4 carbon atoms, such as C₁₋₄ alkyl, especially those offormulae (VII) and (IX).

Examples of compounds of the formula (I) which are of particularinterest for their CNS activity, and for their anti-emetic activity, arethose wherein R₆ contains 5 or more carbon atoms, particularly benzyl,such as those of formulae (VIII) and (X).

The invention therefore also provides a pharmaceutical compositioncomprising a compound of the formula (I), or a hydrate or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier. Such compositions may be adaptedfor oral parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions and the like; the compositions may also be in the form ofsuppositories and the like. Normally, orally administrable compositionsare preferred.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, fillers, tabletting lubricants, disintegrants, andacceptable wetting agents and the like. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, or may bepresented in a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,nonaqueous vehciles (which may include edible oils), preservatives, andif desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound of the formula (I) and a sterile vehicle. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved for injection and filter sterilized beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and bufferingagents can be dissolved in the vehicle. Parenteral suspensions areprepared in substantially the same manner except that the compound issuspended in the vehicle instead of being dissolved and sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

It will of course be realised that the precise dosage used in thetreatment of any of the hereinbefore described disorders will depend onthe actual compound of the formula (I) used, and also on other factorssuch as the seriousness of the disorder being treated.

The invention further provides a method of treatment of maladies inhumans comprising the administration of an effective amount of acompound of the formula (I) or a pharmaceutically acceptable saltthereof. The "effective amount" will depend in the usual way on a numberof factors such as the nature and severity of the malady to be treated,the weight of the sufferer, and the actual compound used.

However by way of illustration, unit doses will suitably contain 0.1 to20 mgs of the compound of formula (I), for example 0.5 to 10 mgs.

Again by way of illustration, such unit doses will suitably beadministered more than once a day, for example 2, 3, 4, 5 or 6 times aday, in such a way that the total daily dose is suitably in the range0.01 to 10 mg/kg per day.

Compounds of the formula (I) have the ability to potentiate the effectof conventional analgesics in migraine treatment when administeredconcurrently with the analgesic.

Thus the invention provides a pharmaceutical composition comprising acompound of the formula (I) and an analgesic.

The compound of the formula (I) and the analgesic, such as aspirin orparacetamol, will be present in the composition in amounts generallysimilar to their usual effective dose.

The composition can be a combination product, for example a tablet orcapsule containing both a compound of the formula (I) and an analgesicfor oral administration, or a twin pack comprising the two activeingredients made up for separate administration.

The invention accordingly provides a method of treatment of migrainecomprising the administration to the sufferer of a compound of theformula (I) and an analgesic.

The following Examples illustrate the preparation of the compounds offormula (I) and the following Descriptions illustrate the preparation ofintermediates thereto.

Nomenclature note: Tropane is 8-methyl-8-azabicyclo [3.2.1]octane andderivatives thereof are named accordingly in the following Descriptions

DESCRIPTION 1 3α,β-amino-8-benzyl-8-azabicyclo-[3,2,1]octane (D1);intermediate for Compounds 1 to 3; mixture of3α-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D26) and3β-amino-8-benzyl-8-azabicyclo[3.2.1]octanec (D4) ##STR16##

8-benzylnortropan-3-one oxime (6 g) was Soxhlet extracted for 15 hoursinto a stirred suspension of lithium aluminium hydride (2.4 g) in dryTHF (150 ml). The mixture was hydrolysed.

Fractional distillation under reduced pressure afforded3-amino-8-benzylnortropane (D1) (4.2 g, 75%) as a mixture of 3α and 3βisomers. b.pt. 107°-10° C./0.2 mm Hg.

DESCRIPTION 2A 3β-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D4);intermediate for Compounds 4 and 5 ##STR17## (a) 8-benzyl-3-nortropanol(D2)

8-benzyl-3-nortropanone (3.9 g) was reduced with lithium aluminiumhydride (1.0 g) in diethyl ether to 8-benzyl-3-nortropanol (D2) by themethod of R. Mirza et al., Nature, 1952, 170, 630. This is claimed byMirza to give stereospecifically the β-isomer but later workers¹ haveshown that a mixture of α and β isomers is produced.

(b) 3β-azido-8-benzylnortropane (D3)

Crude 8-benzyl-3-nortropanol (D2) (3.9 g.) was reacted withsuccessively, triphenylphosphine (4.7 g) and diethyl azodicarboxylate(3.2 g), and diphenylphosphorylazide (5 g) in THF by the method of A. K.Bose et al., Tetrahedron Letters, 1977, 23, 1977, to yield3β-azido-8-benzyl-nortropane (D3) as an oil (2 g, 25%). i.r. 2100 cm⁻¹(γN₃).

(c) 3β-amino-8-benzylnortropane (D4)

To a stirred suspension of lithium aluminium hydride (0.5 g) in diethylether (50 ml) was added a solution of 3β-azido-8-benzylnortropane (D3)(2 g) in diethyl ether (10 ml.), and the reaction was stirred at ambienttemperature for 3 hours. Hydrolysis, extraction with ethyl acetate andremoval of the solvent afforded crude 3β-amino-8-benzylnortropane (1.1g, 60%) used in the procedure of Example 2 without further purification.N.B. The assignment of β-configuration to the azide (D3) and amine (D4)is based on the fact that Compound 5 attained via amine (D4) wasidentical with the β-isomer obtained via the stereospecific routeoutlined in Description 3β and Example 5.

DESCRIPTION 2B 3β-amino-8-(4'-chlorobenzyl)-8-azabicyclo[3.2.1]octane(D5); intermediate for Compound 16

N-(4-chlorobenzyl)-nortropanone (2.02 g., 8.1 mmole) in methanol (100ml) was treated with sodium borohydride (0.75 g.). This was stirred atambient temperature for 12 hours, then poured into saline solution. Itwas made strongly basic with dilute aqueous sodium hydroxide, and theresulting mixture was extracted with ethyl acetate (3×150 ml). Thecombined organic extracts were dried (sodium sulphate), filtered andevaporated to yield a mixture of α- andβ-N-(4-chlorobenzyl)-nortropanols (2.02 g., 99%).

The mixture of isomeric tropanols from above was converted to3β-azido-8-(4-chlorobenzyl)-nortropane by the method described inDescription 2A. Thus N-(4-chlorobenzyl)-nortropanol (3.3 g., 13.1mmoles) was successively treated with triphenylphosphine (3.77 g.),diethylazodicarboxylate (2.49 g) and diphenylphosphoryl azide (4.1 g.)in THF to yield, after work up and chromatography to separate theisomeric azide (3β-azido-8-(4-chlorobenzyl)nortropane (1.1 g., 30.5%) asan oil.

This was reduced with lithium aluminium hydride in ether under refluxfor 12 hours. Hydrolysis, extraction with ethyl acetate and removal ofsolvent afforded crude 3β-amino-8-(4-chlorobenzyl)-nortropane (0.82 g.,82%).

3β-amino-8-(3',4'-dichlorobenzyl)-8-azabicyclo[3.2.1]octane (D6);intermediate for Compound 17 was prepared analogously (32%)

DESCRIPTION 3A 3β-amino-8-methyl-8-azabicyclo[3.2.1]octane (D8),intermediate for Compound 19 ##STR18## (a) Tropinone oxine (D7)

Tropinone (3.68 g; 0.0265 mole) was dissolved in ethanol (50 ml)containing pyridine (4-5 ml) and treated with hydroxylaminehydrochloride (1.90 g). The mixture was heated under reflux for 30minutes, cooled, treated with solid potassium carbonate (ca. 10 g) andwater (ca. 5 ml). The ethanol was removed in vacuo and the mixtureextracted with chloroform (3×150 ml). The combined extracts were dried(K₂ CO₃), filtered and evaporated in vacuo. The resulting solid wasrecrystallised from ethyl acetate/petrol ether 40-60 to yieldtropinoneoxime (3.1 g; 76%) as colourless crystals m.pt 114°-115° C.

(b) 3β-amino-8-methyl-8-azabicyclo[3.2.1]octane (D8)

Tropinone oxime (3.08 g; 0.02 mole) was dissolved in anhydrous amylalcohol (100 ml) and heated to almost boiling. Sodium (ca. 3.0 g) wasadded portionwise over 1 hour then the mixture left to cool overnight.The mixture was treated with 5 N hydrochloric acid (ca. 80 ml), andextracted with ethyl acetate (3×150 ml). The acidic aqueous layer wasseparated, basified with sodium hydroxide and re-extracted with ethylacetate (4×150 ml) and the combined extracts were dried (K₂ CO₃)filtered and evaporated in vacuo to yield (D8) (2.25 g; 80%) as acolourless oil, used without further purification.

DESCRIPTION 3B 3-β-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D4);intermediate for Compound 5 ##STR19##

Similarly, sodium (2 g) was added portionwise over 2 hours to a stirredsolution of 8-benzylnortropan-3-one oxime (0.9 g) in amyl alcohol (20ml) at reflux. The solution was cooled diluted, with diethyl ether andacidified with excess dilute hydrochloric acid. The acid extract waswashed with diethyl ether and then basified with excess potassiumcarbonate. Extraction with ethyl acetate followed by evaporation ofsolvent afforded crude 3β-amino-8-benzylnortropane (d4) (0.85 g) used inthe procedure of Example 5 without purification.

The following intermediates were analogously prepared from thecorresponding oximes:

3α,β-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D9) mixture of3α-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D10); and3β-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D11); intermediates forCompounds 11 and 12 respectively ##STR20## and as oils. The followingintermediates of the general formula ##STR21## were prepared analogously

    ______________________________________                                        Intermediate                  For     Yield                                   No.      R.sub.6        n     Compound                                                                              %                                       ______________________________________                                        D12                                                                                     ##STR22##     0     13      97.6                                    D13                                                                                     ##STR23##     0     14      71                                      D14                                                                                     ##STR24##     0     15      94                                      D15      CH.sub.2 CH.sub.2 Ph                                                                         0     18      83                                      D16      Me             1     22      60                                      D17      Et             0     23      93                                      D18      Pr.sup.n       0     24      97                                      D19      Pr.sup.i       0     25      71                                      D20      Bu.sup.n       0     26      60                                      D21      CH.sub.2 . Pr.sup.i                                                                          0     28      74                                      D22      CH(Me)Et       0     29      50                                      D23                                                                                     ##STR25##     0     30      78                                      D24                                                                                     ##STR26##     0     31      66                                      D30      CH.sub.2 CHCH.sub.2                                                                          0     32                                              ______________________________________                                    

DESCRIPTION 3C 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (D15);intermediate for Compound 21 ##STR27##

N-methyl-9-azabicyclo-[3.3.1]-nonan-3-one oxime (3.25 g., 0.02 mole) wasdissolved in ethanol and hydrogenated over Raney nickel in the presenceof ammonium acetate at 300 p.s.i. at 50° C. for 24 hours. The mixturewas filtered, evaporated in vacuo, dissolved in dilute hydrochloricacid, basified and extracted into ethyl acetate. The combined organiclayers were dried (K₂ CO₃), filtered and evaporated in vacuo to yield3-amino-9-methyl-9-azabicyclo-[3.3.1]-nonane (2.67 g., 90%), usedwithout further purification.

The product is a single diastereomer believed to be the α-isomer.

DESCRIPTION 3D 3α-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D10);intermediate for Compound 11

9-Benzyl-9-azabicyclo-(3.3.1)-nonan-3-one oxime (4.0 g; 0.0164 mole),m.p. 134°, was dissolved in ethanol (100 ml) and hydrogenated at 50°-60°at 250 psi in the presence of Raney nickel. The mixture was filteredafter 24 hours through kieselguhr and evaporated in vacuo. The resultingoil was dissolved in dilute hydrochloric acid (50 ml) extracted withethyl acetate (3×150 ml), the aqueous layer was basified andre-extracted with ethyl acetate (3×150 ml). The combined organicextracts were dried (K₂ CO₃), filtered and evaporated in vacuo to yield3-amino-9-benzyl-9-azabicyclo-[3,3,1]-nonane (2.3 g; 61%), used withoutfurther purification.

DESCRIPTION 4A 3α-amino-8-benzyl-8-azabicyclo[3.2.1]octane, (D6);intermediate for compound 6 ##STR28##

8-benzyl-8-azabicyclo-[3.2.1]-octan-3-one (4.40 g, 0.02 mole) wastreated with excess methylamine in ethanol (50 ml), heated to 60°-70°,then hydrogenated in the presence of pre-reduced platinum (400 mg) togive 8-benzyl-3α-methylamino-8-azabicyclo-[3.2.1]-octane (3.33 g, 72%),m.p. 77°-79°.

DESCRIPTION 4B 3α,β-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane(D27); mixture of 3α-methylamino-8-benzyl-8-azabicylo[3.2.1]octane (D26)and 3β-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane (D28);intermediates for Compounds 6 and 7 respectively ##STR29##

N-benzyl-nortropinone (4.30 g, 0.02 mole) was treated with excessmethylamine in anhydrous toluene. Titanium tetrachloride (50 ml of 10%solution in xylene) was added and the mixture stirred for 2 days. Theresulting mixture was filtered through kieselguhr and evaporated invacuo to give N-benzyl-3-methylimino-nortropane (5.0 g).

A solution of N-benzyl-3-methylimino-notropane (5.0 g) in methanol (100ml) was treated portionwise with sodium borohydride (ca 5.0 g) and themixture left to stir at room temperature for 3 hours. Water (50 ml) wasadded and the mixture extracted with ether (3×100 ml). The combinedorganic extracts were dried (K₂ CO₃), filtered and evaporated in vacuoto give 3-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane (D27) as amixture of the axial (D26) and equatorial (β) (D28) isomers (ca. 60:40)as shown by proton magnetic resonance spectrum.

DESCRIPTION 4C 3α-amino-8-butyl-8-azabicyclo[3.2.1]octane (D29);intermediate for Compound 27 ##STR30##

N-n-butylnortropinone (5.0 g, 0.028 mole) in ethanol (50 ml) was treatedwith ethanolic ammonia and left to stand for 24 hours. The mixture washydrogenated over Raney nickel for 24 hours at 300 p.s.i. in thepresence of ammonium acetate (2.5 g.). The mixture was filtered,evaporated in vacuo, treated with H₂ O, and extracted with ethylacetate. The combined organic extracts were acidified and separated.Basification of the aqueous layer and further extraction with ethylacetate yielded (D29) (2.55 g., 50%), after drying (K₂ CO₃) andevaporation in vacuo which was used without further purification.

DESCRIPTION 5 2-aminomethyl-8-methyl-8-azabicyclo[3.2.1]octane (D31);intermediate for Compound 37 ##STR31## Methyl isocyanide (5.04 g., 0.026mol) was added to (±)-tropan-2-one (2 g., 0.0143 mol) in dimethoxyethane(80 ml) and the solution cooled to 0° C. Ethanol (2 ml) was addedfollowed by addition of potassium tert-butoxide (5.64 g, 6.05 mol). Themixture was then heated at 50° C. for three hours, cooled and pouredinto a saturated potassium carbonate solution (300 ml). This wasextracted with ethyl acetate (3×100 ml) and the combined extracts dried(K₂ CO₃), filtered and evaporated to give a crude oil which wasabosorbed on alumina (40 g, grade 1 neutralised by addition of 10%water) from ethereal solution. The solution was eluted with aprogressively graded mixture of ether, ethyl acetate and methanol togive 8-methyl-8-azabicyclo[3.2]octane-2nitrile (1.1 g-46%) as an oil.

The nitrile (1.1 g) in tetrahydrofuran (20 ml) was added to lithiumaluminium hydride (0.5 g) in tetrahydrofuran (30 ml) and the mixturestirred for three hours. Water (0.5 ml), sodium hydroxide solution (10%)(0.75 ml) and water (1.25 ml) were added successively and the mixturefiltered. The filtrate was dried (K₂ CO₃) and evaporated to give crude(D31) (1 g) as an oil.

The product is a racemate of a single diastereomer, believed to be the(±)-α-isomer.

Description 6 Pentachlorophenyl 5-chloro-2-methoxy-4-methylaminobenzoate(D32) ##STR32## 5-chloro-2-methoxy-4-methyl benzoic acid (2 g., 0.0093mol) in dimethylformamide (50 ml) was treated with pentachlorophenyltrichloroacetate (4.5 g., 0.11 mol) and triethylamine (1.5 ml). Themixture was stirred at room temperature for one hour. Thedimethylformamide was stripped off in vacuo, and the residuerecrystallised from acetone/petroleum to give pentachlorophenyl5-chloro-2-methoxy-4-methylaminobenzoate, m.pt 217°-219° C. EXAMPLE 14-acetamido-5-chloro-2-methoxy-N-(3α,β-[8'-benzyl]-8-azabicyclo[3.2.1]octyl)-benzamide(1) ##STR33##

To 4-acetamido-5-chloro-2-methoxybenzoyl chloride (6 g) in toluene (200ml) and triethylamine (5 ml) was added 3α β-amino-8-benzylnortropane(D1) (4.2 g) (prepared as in Description 1) in toluene (20 ml). Thereaction mixture was stirred at room temperature for 2 hours. Themixture was treated with 2.5 N aqueous sodium hydroxide (20 ml), thetoluene layer was separated and the aqueous layer was extracted withchloroform (3×150 ml) and the combined organic extracts were dried (K₂CO₃). The solvent was removed therefrom and chromatography of theproduct (neutral alumina, Brockman II, ethyl acetate eluant) gave amixture of 3'α and 3'β isomers of (1) as an oil (7.2 g, 84%)

EXAMPLE 2 4-amino-5-chloro-2-methoxy-N-(3'α, 8-[8'-benzyl]8-azabicyclo[3,2,1]octyl)benzamide (2) and 4-amino-5-chloro-2-methoxy-N-(3',α-[8'-benzyl]nortropyl)benzamide (3) ##STR34##

(1) (7.2 g) (prepared as in Example 1) was refluxed with an aqueousethanol (water 10 ml ethanol (100 ml) solution of potassium hydroxide (2g) for 3 hours. The mixture was then cooled to room temperature. Theethanol was removed by rotary evaporation. The residue was extractedwith chloroform. The organic extracts were chromatographed (neutralalumina, Brockman II, ethyl acetate eluant) Bands containing (2) and (3)respectively were obtained, yielding (2) (3.3 g, 50%) and (3) (2.0 g,30%).

(2) was shown by n.m.r. to be a 2:3 weight ratio mixture of the 3'α and3'β isomers, and had a m.pt 159°-70° C.

Compound (3):

m.p.t. 221°-3° C.

n.m.r. (δ, CDCl₃): 8.10 (s, 1H, aryl 6-H); 7.6-7.1 (m, 6H, Ph-H andCONH); 6.30 (s, 1H, aryl 3-H); 4.6-4.2 (m, 3H, --NH₂, CONH.CH═); 3.93(s, 3H, OCH₃); 3.56 (s, 2H, PhCH₂.N═); 3.4-3.1 (m, 2H, ═CH-N(CH₂Ph)-CH═); 2.3-1.5 (m, 8H, ═CH₂).

EXAMPLE 34-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide(4) ##STR35##

A solution of 4-acetamido-5-chloro-2-methoxybenzyl chloride (1.6 g) intoluene (100 ml) and triethylamine (2 ml) was treated with a solution ofcrude 3β-amino-8-benzylnortropane (D4) (1.1 g) (prepared as inDescription 2) in toluene (20 ml), and the reaction was stirred at roomtemperature for 2 hours. The mixture was treated with 2.5 N aqueoussodium hydroxide solution (5 ml), the toluene layer was separated andthe aqueous layer was extracted with ethyl acetate (3×50 ml). Thesolvent was removed from the combined, dried (K₂ CO₃) organic extractsto give an oil which crystallised on trituration with diethyl ether,furnishing4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]nortropyl)benzamide (4)(1.5 g, 70%). m.p.t. 185° C.

EXAMPLE 44-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide(5)

Compound (4) (prepared as in Example 3) (1.5 g) was hydrolysed in anaqueous ethanol (water 2 ml, ethanol 20 ml) solution of potassiumhydroxide (0.5 g) under reflux for 2 hours, and the mixture was thendiluted with water (50 ml), and then cooled to ambient temperature. Theresulting precipitate was collected, dried and recrystallised (ethylacetate/petrol) to give pure4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide(5) (1.1 g, 80%).

m.p.t. 188° C.

n.m.r. (δ CDCl₃): 8.08 (s 1H, aromatic 6-H); 7.60-7.10 (m, 6H, C₆ H₅ andCONH); 6.28(s, 1H, aromatic 3-H); 4.6-4.2 (m, 3H, --NH₂ and CONH.CH═);3.87 (s, 3H, OCH₃); 3.56 (S, 2H, PhCH₂); 3.4-3.1 (m, 2H═CH-N(CH₂Ph)-CH₂); 2.3-1.5 (m, 8H-CH₂).

EXAMPLE 54-Amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]-8-azabicyclo[3.2.1]octyl)benzamide(5)

Following the procedures outlined in Example 4 above, the crude3β-amino-8-benzyl-nortropane (D5) was converted to pure4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]-nortropyl)-benzamide(5)(64%), m.p. 188°-9° C. This was identical to that obtained (n.m.r.and mixed mp.) in Example 4 above.

Nomenclature note: Nortropyl.tbd.(8-azabicyclo-[3,2,1]-octyl).

EXAMPLE 64-Amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]-octyl])-benzamide(19) ##STR36##

4-Acetylamino-5-chloro-2-methoxy benzoic acid (4.0 g; 0.016 mole) wasdissolved in thionyl chloride (40 ml) at 30°, evaporated in vacuo andazeotroped twice with anhydrous toluene (ca. 100 ml). The resulting4-acetylamino-5-chloro-2-methoxy benzoyl chloride was redissolved inwarm anhydrous toluene (ca. 100 ml) treated with triethylamine (5 ml)and 3β-aminotropane (prepared above). The reaction mixture was stirredat room temperature for 2 hours. The mixture was treated with 2.5 Nsodium hydroxide (20 ml), the toluene layer was separated and theaqueous layer extracted with chloroform. The combined extracts wereevaporated in vacuo and the resulting solid refluxed with an aqueousethanol (water 5 ml; ethanol 50 ml) solution of potassium hydroxide (2.5g) for 11/2 hours. The mixture was cooled, ethanol removed in vacuo andthe mixture extracted with warm chloroform (5×100 ml). The combinedorganic extracts were dried (K₂ CO₃) filtered and evaporated in vacuo.Recrystallisation of the resulting solid gave4-amino-5-chloro-2-methoxy-N-(3'β-[8-methyl-8-azabicyclo[3.2.1]-octyl])-benzamide(1.3 g; 30%) as colourless microcrystals, m.p. 249°-250°.

The following compounds were prepared in an analogous manner:

Compounds in Table B with A suffixed are the 4-acetylamino condensationproducts, prior to base hydrolysis to give the corresponding compound ofthe unsuffixed number.

                                      TABLE B                                     __________________________________________________________________________     ##STR37##                                                                    Compound                                                                            From               isomer*    m.pt                                      No.   Intermediate                                                                         R.sub.6   u *   R.sub.5                                                                          R.sub.3                                                                           °C.                                __________________________________________________________________________    6     D+26                                                                                  ##STR38##                                                                              0 α                                                                           Me NH.sub. 172.5                                 11    D 10                                                                                  ##STR39##                                                                              1 α                                                                           H  NH.sub.2                                                                          199                                       13    D12                                                                                   ##STR40##                                                                              0 β                                                                            H  NH.sub.2                                                                          213-5                                     14    D13                                                                                   ##STR41##                                                                              0 β                                                                            H  NH.sub.2                                                                          175-8                                     15    D14                                                                                   ##STR42##                                                                              0 β                                                                            H  NH.sub.2                                                                          164-6                                     16    D5                                                                                    ##STR43##                                                                              0 β                                                                            H  NH.sub.2                                                                          212-3                                     17    D6                                                                                    ##STR44##                                                                              0 β                                                                            H  NH.sub.2                                                                          191-5                                     18    D15    CH.sub.2 CH.sub.2 Ph                                                                    0 β                                                                            H  NH.sub.2                                                                          222                                       18A   D15    CH.sub.2 CH.sub.2 Ph                                                                    0 β                                                                            H  NHAc                                                                              224                                       20    D26    Me        0 α                                                                           H  NH.sub.2                                                                          219-220                                   20A   D26    Me        0 α                                                                           H  NHAc                                                                              178-9                                     21    D25    Me        1  α*                                                                         H  NH.sub.2                                                                          218-220                                   22    D16    Me        1  β*                                                                          H  NH.sub.2                                                                          208-9                                     23.sup.+                                                                            D17    Et        0 β                                                                            H  NH.sub.2                                                                          187                                       23A   D17    Et        0 β                                                                            H  NHAc                                                                              157                                       24    D18    Pr.sup.n  0 β                                                                            H  NH.sub.2                                                                          205                                       24A   D18    Pr.sup.n  0 β                                                                            H  NHAc                                                                              140                                       25    D19    Pr.sup.i  0 β                                                                            H  NH.sub.2                                                                          183                                       26    D20    Bu.sup.n  0 β                                                                            H  NH.sub.2                                                                          224-6                                     27    D29    Bu.sup. n 0 α                                                                           H  NH.sub.2                                                                          205-6                                     28    D21    CH.sub.2 Pr.sup.i                                                                       0 β                                                                            H  NH.sub.2                                                                          206-7                                     29    D22    CH(Me)Et  0 β                                                                            H  NH.sub.2                                                                          195-7                                     30    D23                                                                                   ##STR45##                                                                              0 β                                                                            H  NH.sub.2                                                                          253-4                                     31    D24                                                                                   ##STR46##                                                                              0 β                                                                            H  NH.sub.2                                                                          278                                       31A   D24                                                                                   ##STR47##                                                                              0 β                                                                            H  NHAc                                                                              207                                       32    D30    CH.sub.2 CHCH.sub.2                                                                     0 β                                                                            H  NH.sub.2                                                                          173-5                                     __________________________________________________________________________     + Prepared as described in Description                                          Prepared as described in Description                                        .sup.+ as the crystalline                                                     *provisional assignment                                                  

The following Compounds may be prepared analogously: ##STR48##

EXAMPLE 74-Amino-5-chloro-2-methoxy-N-methyl-N-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl)benzamide,(6), and4-amino-5-chloro-2-methoxy-N-methyl-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl)benzamide,(7) ##STR49##

Treatment of (D 27) prepared as in Description 4B with4-acetylamino-5-chloro-2-methoxy-benzoyl chloride and hydrolysis asoutlined in Example 6 gave4-amino-5-chloro-2-methoxy-N-methyl-N-(3β-[8-benzyl-8-azabicyclo-[3.2.1])benzamide(7), m.p. 180° and4-amino-5-chloro-2-methoxy-N-methyl-N-(3α-[8-benzyl-8-azabicyclo-[3,2,1]-octyl])-benzamide(6), m.p. 173° separated by chromatographic elution with ether/ethylacetate from silica.

The latter compound was identical with Compound 6 prepared in Example 6from the α-amino intermediate (D 26), in turn prepared as in Description4A.

EXAMPLE 85-Sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl]-8'-azabicyclo-[3.2.1]-octyl)-benzamide(8) ##STR50##

5-sulphamoyl-2-methoxybenzoic acid (2.0 g., 0.009 mole) was dissolved inanhydrous dimethylformamide (20 ml), treated with triethylamine (0.83 g,0.009 mole) and cooled to 0°. Ethyl chloroformate (0.95 g., 0.009 mole)was added dropwise and the solution left to stir for 15 minutes.3β-Amino-8-benzyl-8-azabicyclo-[3.2.1]-octane (D4) (1.9 g., 0.09 mole)[prepared as outlined in Description 3B] was added in one portion at 0°.The mixture was left to stand overnight, evaporated to dryness, treatedwith water (5 ml) and dilute ammonia (10 ml) to give5-sulphamoyl-2-methoxy-N-(3'β-[8-benzyl-8-azabicyclo-[3,2,1]-octyl])-benzamide(38%), m.p. 213°-214°.

EXAMPLE 92-Methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide (9)##STR51##

3β-Amino-8-benzylnortropane (D4) (1.01 g., 4.67 mmoles) in dry toluene(15 ml) was added to a solution of 2-methoxybenzoyl chloride (made bythe reaction of thionyl chloride with 0.78 g. anisic acid) in drytoluene containing 2 ml of triethylamine. The mixture was stirred atambient temperature for 12 hours then poured into water which was madealkaline by the addition of solid sodium carbonate. The mixture wasextracted with ethyl acetate (3×200 ml). Subsequent drying (Na₂ SO₄) andremoval of solvent followed by chromatography on silica gel gave thepure 2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo-[3.2.1]-octyl])benzamide(1.03 g., 63%) as an oil, m.pt. (HCl salt) 269° C.

EXAMPLE 104-Amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])-benzamidemethobromide (10) ##STR52##

Bromomethane (5 ml) was added to4-amino-5-chloro-2-methoxy-N-[3β'-(8'-benzyl-nortropyl)]-benzamide (6)(1.0 g) in anhydrous acetone (50 ml) and the solution allowed to standat ambient temperature for 3 days. The solid produced was filtered offand recrystallised from methanol/ethyl acetate to give4-amino-5-chloro-2-methoxy-N-[3β-(8-benzyl-8-azabicyclo[3.2.1]octyl)-benzamidemethobromide (0.63 g; 53% m.p. 222 -5°).

EXAMPLE 114-Amino-5-chloro-2-methoxy-N-(3'α-[9'-azabicyclo[3.3.1]nonyl)benzamide(11) and4-amino-5-chloro-2-methoxy-N-(3'β-[9'-benzyl-9'-azabicyclo-[3.3.1]-nonyl])-benzamide(12) ##STR53##

Reaction of 3αβ-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D9) preparedas in Description 3B with 4-acetylamino-5-chloro-2-methoxy-benzoylchloride and hydrolysis as outlined in Example 6 gave 80-90%4-amino-5-chloro-2-methoxy-N-(3'β-[9'-benzyl-9'-azabicyclo-[3.3.1]-nonyl)-benzamide(12) m.p. 224°-225° and 10-20%4-amino-5-chloro-2-methoxy-N-(3'α-[9'-benzyl-9'-azabicyclo-[3,3,1]-nonyl)-benzamide(11) m.p. 199°, separated by chromatographic elution from silica withethyl acetate/petrol-ether 60°-80°.

The latter compound, m.p. 199°, is identical to Compound 11 prepared inExample 6 from the α-amine (D10), in turn prepared as in Description 3D.

EXAMPLE 124-Amino-5-chloro-2-methoxy-N(2'-(±)-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide(37)

This compound was prepared analogously to Example 6 from (D 31).

M.pt. 218°-9° C.

The product is a racemate of a single diastereomer, believed to be the(±)-α-isomer.

EXAMPLE 135-chloro-2-methoxy-4-methylamino-N-[3β-(8'-benzyl-9'-azabicyclo-(3.2.1)octyl)]benzamide(33) ##STR54##

Pentachlorophenyl 5-chloro-2-methyoxy-4-methylamino)benzamide (D32) (1g.) was treated with 3β-amino-8-benzyl-8-azabicyclo(3.2.1)octane (0.47g) in dimethyl formamide (15 ml) at 80° for 24 hours. The mixture wasevaporated to a thin film, then poured into stirred water. The whitecrystals were filtered, dried in vacuo and chromatographed on 5%deactivated alumina (Brockman 1) using ethyl acetate as eluant. Therecovered material was recrystallised from ethyl acetate and lightpetroleum 60/80 to give5-chloro-2-methoxy-4-methylamino-N[3β-(8'-benzyl-8'-azabicyclo(3.2.1)octyl)]benzamide,m.pt 156°-157° C.

PHARAMACOLOGICAL DATA

The following Section illustrates the pharmacological activity ofcompounds of the formula (I).

I. Dopamine Receptor Blocking Activity in the Central Nervous System (a)Inhibition of apomorphine induced stereotype behaviour in the rat

(method of Ernst (1967), Psychopharmacologia (Berl.) 10 316-323). TableI shows the dose for complete inhibition.

Compounds marked IA () are inactive at the dose in the brackets, mg/Kgs.c.

(b) Inhibition of apomorphine induced climbing in the mouse

The test is based on that described by Protais, P., Constantin, J. andSchwartz J. C. (1976), Psychopharmacology, 50, 1-6.

Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire cage(inverted food hopper--11×7.5×18 cm high). Mice acclimatised in theirhome cages in groups of 5 are placed under the hoppers immediately afterthe injection of apomorphine 1 mg/kg s.c. At 10, 20 and 30 minutes afterinjection climbing behaviour is scored. The mice are observed for 30seconds and scored according to the position they spend the majority oftime in, score 0--four paws on floor of cage; score 1--fore paws only onwalls; score 2--all paws on wall of cage. The scores at all 3 times andfor each mouse are summed and mice drug treated orally compared to micereceiving apomorphine only. A saline only treated group is also includedand any score, generally <5% of maximum taken into account.

Table I shows the dose for complete inhibition, or the ED₅₀. Compoundsmarked IA were inactive at 10 mg/Kg p.o.

(c) In vitro displacement of radiolabelled spiroperidol from dopaminereceptor membranes

[3H]-spiroperidol has been shown to bind with high affinity to dopaminereceptors in the brain (Greese, I., Schneider, R. and Snyder, S. H.,European J. Pharmac., 46 [1977], 377-381; Leysen, J. E., Gommeren, W.and Laduron, P. H. Biochem. Pharmac., 27, [1978]. 307-316). Therefore acompound which displaces this ligand from dopamine receptor membranesmay have neuroleptic properties.

Male Hooded Lister rats (200-300 g) are decapitated and the caudatenucleus is quickly dissected out. This is homogenised in ice cold Trisbuffer (pH 7.7 at 25° C.) at a concentration of 10 mg/ml wet weight oftissue. The test compound (at 10⁻⁵ M) or spiroperidol (standard curvefrom 10⁻⁵ to 10⁻⁹ M) is added to the assay tubes followed by 0.5 nM [³H]-spiroperidol. This is mixed with 500 μl of the membrane preparationand the assay tubes are incubated for 15 minutes at 37° C. After thisperiod 4 ml ice cold Tris buffer is added to each tube and the solutionsare filtered through pre-soaked glass fibre filters. The filter iswashed twice with 4 ml of the buffer and then transferred to ascintillation vial for counting. Single concentration results are givenas a percentage of [³ H]-spiroperidol displaced. Table I shows thepercentage displacement at 10⁻⁵ M concentration of the compound, or theconcentration for 50% displacement (ED₅₀). Compounds displacing lessthan 50% at 10⁻⁵ M are not shown in Table I.

II. Anti-emetic activity in the dog

Compounds were administered subcutaneously 30 minutes prior toadministration of a standard dose of apomorphine HCl (0.1 mg/kgsubcutaneously) and the vomiting response compared to that obtained whenthe same animals were dosed with apomorphine HCl and vehicle only. Thedose that totally inhibited the vomiting response was determined in thesame instances, the ED₅₀ in others.

III. Gastric Activity (A) Increase in intragastric pressure in the rat

Intragastric pressure changes were recorded from previously starvedconscious but restrained rats using a saline filled catheter insertedinto the lumen of the stomach via a permanent gastric fistula. Thecatheter was connected to a physiological pressure transducer andpressure changes recorded on a hot wire pen recorder. In each animal apre-dose period of 40 minutes was allowed to obtain a measure ofspontaneous activity. An index of activity was obtained by measuring theaverage height of pressure waves during 10 minute periods. Values for 4such periods were obtained during assessment of spontaneous activity andfor the 40 minute period after the subcutaneous administration of thecompounds. Students `t` test was applied to the difference in averagevalues obtained for spontaneous and post-compound activity.

Table II shows the miniumum dose for activity. Compounds marked IA ()are inactive at the dose in the brackets, mg/Kg s.c.

(b) Increase in gastric emptying: reversal of apomorphine induced delayin gastric emptying in the rat

Rats equipped with chromic gastric fisulae were used and it was throughthis that 5 ml of a test meal (5 ml phosphate buffer at pH 9) wasadministered and recovered. The % recovery of the standard meal afterremaining in the stomach for 10 minutes was taken as an index of gastricemptying. Delay in gastric emptying was induced by the administration ofapomorphine HCl (5 mg/kg subcutaneously) which was given 15 minutesprior to the subcutaneous administration of the compound. The %recoveries of the test meal were determined at 15-25 and 45-55 minutespost-dosing with the compound and compared with vehicle only dosedanimals set up simultaneously. Six animals were used for each group.

Table II shows the % increase in gastric emptying for 10 mg/kg s.c. ofthe compound.

In addition the % recoveries for compound 2 are shown in the Tableimmediately below.

                  TABLE                                                           ______________________________________                                                      % Recovery of test meal.                                                      Mean values ± S.E. of mean                                                 Time interval post dosing                                                     with vehicle or compounds                                       Treatment       15-25 mins. 45-55 mins.                                       ______________________________________                                        (1) Apomorphine + vehicle                                                                     72.4 ± 5.1                                                                             60.7 ± 7.3                                     (2) Apomorphine + vehicle                                                                     37.4 ± 6.7**                                                                           18.3 ± 1.1***                                    (2) 10 mg/kg s.c.                                                           ______________________________________                                         Significantly different from apomorphine + vehicle group set up               simultaneously **p < 0.01 ***p < 0.001.                                  

At 10 mg/kg subcut. the % recovery of test meal was significantlydecreased at both the 15-25 and 45-55 minute time intervals andtherefore gastric emptying was increased.

Compound 5 significantly increases gastric emptying at a dose of 0.05mg/kg s.c.

                  TABLE I                                                         ______________________________________                                                    I(b)                                                              I(a)        Anti-Climbing                                                     Dose        Activity      I(c)                                                Inhibiting  Dose mg/kg    Spiroperidol                                        Stereotype  p.o.          Displacement                                        Com-  Behaviour Complete        %      ED.sub.50                              pound mg/kg s.c.                                                                              Inhibition                                                                             ED.sub.50                                                                            at 10.sup.-5 M                                                                       M × 10.sup.-7                    ______________________________________                                        2     10                                                                      3     50                                                                      5     0.05               0.03                                                 6     IA(50)    IA                                                            8               IA                                                            9               10                                                            10                IA(2)                                                       11    IA(50)    IA                                                            12     0.5       2              53                                            13                       0.12   54                                            14              10                                                            15              10                                                            16               2                                                            18    IA(50)    IA                     6                                      19    IA(25)    IA              64                                            21    IA(50)    10                                                            22    IA(25)    IA                                                            23    IA(25)    IA                                                            24    IA(25)    IA                                                            25    IA(25)    IA                                                            26    t                  2.9           4                                      27    IA(10)    IA              66                                            28                                                                            30    *          5                     2 × 10.sup.-1                    31              IA                                                            ______________________________________                                          lower levels not tested;                                                     t slight at 1:                                                                *slight at 0.05                                                          

For the sake of completeness it should be mentioned that single compoundtests have shown Compound 5 to have anti-obesity activity and Compound20 to have anti-arrhythmic activity.

Toxicity

In the tests reported above no toxic effects were observed.

We claim:
 1. A compound of the formula (I) and pharmaceuticallyacceptable salts thereof: ##STR55## wherein: R₁ is a C₁₋₆ alkoxygroup;R₂ is hydrogen, halogen, CF₃, C₂₋₇ acyl, C₂₋₇ acylamino, or aminoor aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups,or nitro; R₃ is aminosulphone optionally substituted by one or two C₁₋₆alkyl groups, or C₁₋₆ alkylsulphone; R₅ is hydrogen or C₁₋₆ alkyl; R₆ isC₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 0 to 2 and R₇ is a C₃₋₈cycloalkyl group, or a group --(CH₂)_(t) R₈ where t is 1 or 2 and R₈ isC₂₋₅ alkenyl or a phenyl group optionally substituted by one or twosubstituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl andhalogen; and n, p and q are independently 0 to
 2. 2. A compoundaccording to claim 1 wherein:R₁ is a C₁₋₆ alkoxy group; R₂ is hydrogen,halogen, CF₃, C₂₋₇ acyl, amino, C₂₋₇ acyl amino or aminocarbonyloptionally substituted by one or two C₁₋₆ alkyl groups; or nitro; R₃ isaminosulphone optionally substituted by one or two C₁₋₆ alkyl groups, orC₁₋₆ alkylsulphone; R₅ is hydrogen or C₁₋₆ alkyl; R₆ is C₁₋₇ alkyl or agroup --(CH₂)_(s) R₇ where s is 1 or 2 and R₇ is a C₃₋₈ cycloalkylgroup, or a phenyl group optionally substituted by one or twosubstitutents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl andhalogen; and n, p and q are independently 0 to
 2. 3. A compoundaccording to claim 2, wherein R₅ is hydrogen.
 4. A compound according toclaim 2, wherein R₂ is hydrogen.
 5. A compound according to claim 2,wherein R₂ is 4-amino or 4-acylated amino.
 6. A compound according toclaim 2, wherein R₃ is in the 5-position.
 7. A compound according toclaim 6, wherein R₃ is aminosulphone or methylsulphone.
 8. A compoundaccording to claim 2, wherein the moiety of formula (IV): ##STR56## ifof formula (V): ##STR57##
 9. A compound according to claim 8, wherein R₅is hydrogen.
 10. A compound according to claim 8, wherein R₂ ishydrogen, 4-amino or 4-acylated amino and R₃ is in the 5-position.
 11. Acompound according to claim 10, wherein p is 0 or 1 and q is 0 or
 1. 12.A compound according to claim 11, wherein the CO-NH-- is attached to themoiety of formula (V) at the position para to the N atom in the moietyof formula (V).
 13. A compound according to claim 12, wherein theCO-NH-- is in the β orientation to the moiety of formula (V).
 14. Acompound according to claim 13, wherein R₆ is C₁₋₄ alkyl.
 15. A compoundaccording to claim 13, wherein R₆ is C₅₋₇ alkyl or benzyl. 16.5-Sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl]-8'-azabicyclo-[3.2.1]-octyl)-benzamide,or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition having dopamine antagonist activity comprising a dopamineantagonist effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.
 18. A method of treatment of humanssuffering from emesis, impaired gastro-intestinal motility or disordersof the central nervous system, which method comprises the administrationto the sufferer of an effective amount of a compound as claimed in claim1 sufficient to overcome the emesis, impaired gastro-intestinal motilityor disorder of the central nervous system.
 19. A compound according toclaim 2, wherein R₁ is methoxy, ethoxy or n or iso-propoxy.
 20. Acompound according to claim 19 wherein R₁ is methoxy.
 21. A compoundaccording to claim 2, or a pharmaceutically acceptable salt thereof,wherein R₂ is in the 4-position relative to the carbonyl side-chain. 22.A compound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein R₂ is 4-amino or 4-acylated amino.
 23. A compoundaccording to claim 2, or a pharmaceutically acceptable salt thereof,wherein R₃ is in the 5-position relative to the carbonyl side-chain. 24.A compound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein R₃ is 5-aminosulphone.
 25. A compound according toclaim 2, or a pharmaceutically acceptable salt thereof, wherein R₃ is5-methylsulphone.
 26. A compound according to claim 2, or apharmaceutically acceptable salt thereof, the amide and side-chainnitrogen atoms separated by a minimum of 2 or 3 carbon atoms.
 27. Acompound according to claim 2, or a pharmaceutically acceptable saltthereof, the amide and side-chain nitrogen atoms separated by a minimumof 3 carbon atoms.
 28. A compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein R₅ is hydrogen,methyl, ethyl, n- or iso-propyl or n-, sec- or tert-butyl.
 29. Acompound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein R₅ is hydrogen.
 30. A compound according to claim 2, ora pharmaceutically acceptable salt thereof, wherein R₆ is methyl, ethyl,n- or iso-propyl, or n-, sec-, iso- or tert-butyl, n-pentyl, n-hexyl orn-heptyl.
 31. A compound according to claim 2, or a pharmaceuticallyacceptable salt thereof, wherein the bond between the benzamide moietyand the cyclic side-chain is equatorial.
 32. A compound according toclaim 12, or a pharmaceutically acceptable salt thereof, wherein thepharmaceutically acceptable salts are acid addition salts or quaternaryammonium salts.
 33. A pharmaceutical composition having dopamineantagonist activity which comprises a dopamine antagonist effectiveamount of the compound5-sulphamoyl-2-methoxy-N-(3'β-[8'benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.
 34. A pharmaceutical compositionaccording to claim 17, wherein the compound of claim 17 has a balancebetween peripheral and central action useful in the treatment ofdisorders related to impaired gastrointestinal motility includingretarded gastric emptying, dyspepsia, flatulence, oesophagal reflux,peptic ulcer and emesis and having anti-psychotic activity.
 35. Apharmaceutical composition according to claim 17 formulated for oral orparenteral administration.
 36. A pharmaceutical composition according toclaim 35, wherein the oral or parenteral administrable form comprisescompressed tablets, capsules, oral liquids, powders, granules, lozenges,reconstitutable powders and injectable and infusible solutions orsuspensions and syrups and suppositories.
 37. A pharmaceuticalcomposition according to claim 36, wherein the composition is formulatedin unit-dosage, orally-administrable form of which each unit dosagecontains an effective amount of a compound of formula (I).